Liver Transplantation
Conditions
Keywords
Everolimus,, liver transplantation,, early introduction,, renal function
Brief summary
The aims of the study was to evaluate the safety and efficacy of early introduction one month post-transplantation of everolimus associated to EC-MPS with tacrolimus discontinuation in de novo liver transplant recipients and to evaluate if it leads to a better renal function 6 month post-transplantation compared to standard treatment associating tacrolimus and EC-MPS. The renal function was estimated by glomerular filtration rate.
Interventions
DRUGtacrolimus
Arm 1 : tacrolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to month 6 post-transplantation. Arm 2 : tacolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to 16 weeks post-transplantation at the latest.
DRUGeverolimus
Arm 1: no everolimus Arm 2: everolimus (C0 6-10 ng/ml) from randomization to month 6 post-transplantation
DRUGBasiliximab
Basiliximab was supplied to the participating centers as marketed, i.e. in packs containing one vial of 20-mg powder, and water for injection (WFI). 20 mg at D0 and D4
DRUGMycophenolic Acid
Dose of 1440 mg/day from transplantation to month 6 post- transplantation
DRUGCorticosteroids
Administration of oral corticosteroid therapy was at the discretion of the centers according to their usual practice
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Man or woman aged 18 years or greater, recipient of a primary liver transplant from a deceased donor with whole or split liver Key
Exclusion criteria
* Patient recipient of multiple solid organ or islet cell tissue transplants, or have previously received an organ or tissue transplant * Recipient of a liver from a living donor or cadaveric non heart beating donor * ABO incompatible transplant graft * Transplantation following autoimmune liver hepatitis, primitive sclerosing cholangitis or primitive biliary cirrhosis * Estimated glomerular filtration rate ≤ 30ml/min at selection * History of malignancy within the 5 past years, other than non-metastatic basal or squamous cell carcinoma and hepatocellular carcinoma * Alpha-foeto-protein \> 1000 ng/ml (only in case of hepatocellular carcinoma)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (Randomization) in Renal Function | Baseline, Week 24 | Change in renal function was measured by change in glomerular filtration rate (GFR). GFR calculated using the abbreviated modification of diet in renal disease (aMDRD) formula. GFR in mL/min/1.73m\^2 for men of non-black ethnicity: 186 \* \[C/88\]\^-1.154 \* \[A\]\^-0.023\*G\*R ; C = serum creatinine (in μmol/L); A = Age (in years). G = 0.742 when the patient is a women; Otherwise G=1 R= 1.21 when the patient was of black ethnicity; Otherwise R = 1 Baseline was Day 28 visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Treatment Failures | At week 12 and week 24 | Incidence of treatment failures, assessed with composite criterion including treated biopsy proven acute rejection (tBPAR) with a rejection activity index (RAI) according to Banff classification \>3, graft loss or death at 6 months. Biopsy proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted. The graft was presumed to be lost on the day the patient was registered again on the waiting list, or the day he/she received a new graft. |
| Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR) | at 12 week and 24 week | Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy. |
| Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification | at 12 week and 24 week | Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy. The severity of BPAR was categorized as : Mild (Banff grade I, RAI = 4 and 5) Moderate (Banff grade II, RAI = 6 and 7) Severe (Banff grade III, RAI = 8 and 9) Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted. |
| Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3 | At 24 weeks | Biopsy proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted. The patients with treated or untreated BPAR having RAI score \> 3 were reported in this end point. |
| Change From Baseline (Randomization) in Serum Creatinine | Baseline, Week 24 | Change in serum creatinine concentrations from baseline (randomization) to week 24 post-randomization was one of the efficacy assessments of renal function. Baseline was Day 28 visit. |
| Number of Patients With Death or Graft Loss | at week 24 | The graft was presumed to be lost on the day the patient was registered again on the waiting list, or the day he/she received a new graft. |
| Change From Baseline (Randomization) in Creatinine Clearance Estimated Using the Adjusted Cockcroft-Gault Formula | Baseline, Week 24 | Creatinine clearance by the Cockcroft-Gault formula is computed in mL/min/1.73m\^2 from the creatinine clearance in mL/min by multiplying it by 1.73 and dividing it by the body surface area Baseline was Day 28 visit. |
| Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by Abbreviated Modification of Diet in Renal Disease (MDRD) Formula | Baseline, Week 24 | Change in glomerular filtration rate was calculated using the MDRD abbreviated formula. GFR in mL/min/1.73m\^2 for men of non-black ethnicity: 186 \* \[C/88\]\^-1.154 \* \[A\]\^-0.023\*G\*R ; C = serum creatinine (in μmol/L); A = Age (in years). G = 0.742 when the patient is a women; Otherwise G=1 R= 1.21 when the patient was of black ethnicity; Otherwise R = 1 Baseline was Day 28 visit. |
| Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by CKD-EPI Formula | Baseline, Week 24 | GFR estimated by using the Chronic kidney disease- epidemiology (CKD-EPI) formula: eGFR (mL/min/1.73m\^2) = 141 \* min(C/K,1)\^ α \* max(C/K,1)\^-1.209 \* 0.993\^A \* 1.1018 (if male) \* 1.159 (if black) where C = serum creatinine (in mg/dL) ; A = Age (in years); K = 0.7 for women and 0.9 for men; α = -0.329 for women and -0.411 for men. Baseline was Day 28 visit. |
| Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System | At Week 24 | Kidney disease outcomes quality initiative (K/DOQI) classification is based on glomerular filtration rate (GFR), abbreviated MDRD formula (mL/min/1.73m\^2) : Stage 1 : GFR \>= 90; Stage 2 = GFR was between 60-89; Stage 3 = GFR was between 30-59 ; Stage 4 = GFR was between 15-29; Stage 5 = GFR was \< 15 (or dialysis) |
| Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation | Baseline to 24 weeks | Baseline was Day 28 visit. This endpoint reports patients with total adverse events (any), serious adverse events, death and premature discontinuation. |
| Change From Baseline (Randomization) in Urine Protein/Creatinine Ratio | Baseline, week 24 | Change in urine protein/creatinine ratio from baseline (randomization) to week 24 post-randomization was one of the efficacy assessments of renal function. Baseline was Day 28 visit. |
Countries
France
Participant flow
Pre-assignment details
Total 188 patients were randomized
Participants by arm
| Arm | Count |
|---|---|
| Tacrolimus From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids | 95 |
| Everolimus (RAD001) From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids.
From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest). | 93 |
| Total | 188 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory values | 1 | 0 |
| Overall Study | Administrative Problem | 1 | 1 |
| Overall Study | Adverse Event | 3 | 16 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Graft loss | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 3 |
| Overall Study | Unsatisfactory therapeutic effect | 0 | 1 |
Baseline characteristics
| Characteristic | Tacrolimus | Everolimus (RAD001) | Total |
|---|---|---|---|
| Age, Continuous | 55.5 Years STANDARD_DEVIATION 8.24 | 56.5 Years STANDARD_DEVIATION 8.59 | 56.0 Years STANDARD_DEVIATION 8.41 |
| Sex: Female, Male Female | 14 Participants | 14 Participants | 28 Participants |
| Sex: Female, Male Male | 81 Participants | 79 Participants | 160 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 68 / 94 | 64 / 90 |
| serious Total, serious adverse events | 28 / 94 | 42 / 90 |
Outcome results
Primary
Change From Baseline (Randomization) in Renal Function
Change in renal function was measured by change in glomerular filtration rate (GFR). GFR calculated using the abbreviated modification of diet in renal disease (aMDRD) formula. GFR in mL/min/1.73m\^2 for men of non-black ethnicity: 186 \* \[C/88\]\^-1.154 \* \[A\]\^-0.023\*G\*R ; C = serum creatinine (in μmol/L); A = Age (in years). G = 0.742 when the patient is a women; Otherwise G=1 R= 1.21 when the patient was of black ethnicity; Otherwise R = 1 Baseline was Day 28 visit.
Time frame: Baseline, Week 24
Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value a Day 28 and a posterior value were available. The last observation carried forward (LOCF) is used as imputation of missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tacrolimus | Change From Baseline (Randomization) in Renal Function | -13.29 mL/min/1.73m^2 | Standard Error 2.75 |
| Everolimus (RAD001) | Change From Baseline (Randomization) in Renal Function | 1.05 mL/min/1.73m^2 | Standard Error 2.81 |
p-value: <0.000195% CI: [-21.34, -7.34]ANCOVA
Secondary
Change From Baseline (Randomization) in Creatinine Clearance Estimated Using the Adjusted Cockcroft-Gault Formula
Creatinine clearance by the Cockcroft-Gault formula is computed in mL/min/1.73m\^2 from the creatinine clearance in mL/min by multiplying it by 1.73 and dividing it by the body surface area Baseline was Day 28 visit.
Time frame: Baseline, Week 24
Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value at D28 and a posterior value were available. The last observation carried forward (LOCF) is used as imputation of missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tacrolimus | Change From Baseline (Randomization) in Creatinine Clearance Estimated Using the Adjusted Cockcroft-Gault Formula | -9.0 mL/min/1.73m^2 | Standard Deviation 30.63 |
| Everolimus (RAD001) | Change From Baseline (Randomization) in Creatinine Clearance Estimated Using the Adjusted Cockcroft-Gault Formula | 0.7 mL/min/1.73m^2 | Standard Deviation 25.65 |
Secondary
Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by Abbreviated Modification of Diet in Renal Disease (MDRD) Formula
Change in glomerular filtration rate was calculated using the MDRD abbreviated formula. GFR in mL/min/1.73m\^2 for men of non-black ethnicity: 186 \* \[C/88\]\^-1.154 \* \[A\]\^-0.023\*G\*R ; C = serum creatinine (in μmol/L); A = Age (in years). G = 0.742 when the patient is a women; Otherwise G=1 R= 1.21 when the patient was of black ethnicity; Otherwise R = 1 Baseline was Day 28 visit.
Time frame: Baseline, Week 24
Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value at D28 and a posterior value were available. The last observation carried forward (LOCF) is used as imputation of missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tacrolimus | Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by Abbreviated Modification of Diet in Renal Disease (MDRD) Formula | -11.8 mL/min/1.73m^2 | Standard Deviation 34.01 |
| Everolimus (RAD001) | Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by Abbreviated Modification of Diet in Renal Disease (MDRD) Formula | 0.1 mL/min/1.73m^2 | Standard Deviation 32.59 |
Secondary
Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by CKD-EPI Formula
GFR estimated by using the Chronic kidney disease- epidemiology (CKD-EPI) formula: eGFR (mL/min/1.73m\^2) = 141 \* min(C/K,1)\^ α \* max(C/K,1)\^-1.209 \* 0.993\^A \* 1.1018 (if male) \* 1.159 (if black) where C = serum creatinine (in mg/dL) ; A = Age (in years); K = 0.7 for women and 0.9 for men; α = -0.329 for women and -0.411 for men. Baseline was Day 28 visit.
Time frame: Baseline, Week 24
Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value at D28 and a posterior value were available. The last observation carried forward (LOCF) is used as imputation of missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tacrolimus | Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by CKD-EPI Formula | -6.9 mL/min/1.73m^2 | Standard Deviation 20.11 |
| Everolimus (RAD001) | Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by CKD-EPI Formula | 2.4 mL/min/1.73m^2 | Standard Deviation 22.18 |
Secondary
Change From Baseline (Randomization) in Serum Creatinine
Change in serum creatinine concentrations from baseline (randomization) to week 24 post-randomization was one of the efficacy assessments of renal function. Baseline was Day 28 visit.
Time frame: Baseline, Week 24
Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value at D28 and a posterior value were available. The last observation carried forward (LOCF) is used as imputation of missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tacrolimus | Change From Baseline (Randomization) in Serum Creatinine | 7.2 µmol/L | Standard Deviation 36 |
| Everolimus (RAD001) | Change From Baseline (Randomization) in Serum Creatinine | -1.3 µmol/L | Standard Deviation 38.53 |
Secondary
Change From Baseline (Randomization) in Urine Protein/Creatinine Ratio
Change in urine protein/creatinine ratio from baseline (randomization) to week 24 post-randomization was one of the efficacy assessments of renal function. Baseline was Day 28 visit.
Time frame: Baseline, week 24
Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom urine protein and creatinine value at day 28 and a posterior value were available. LOCF applied.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tacrolimus | Change From Baseline (Randomization) in Urine Protein/Creatinine Ratio | -2.3 mg/mmol | Standard Deviation 27.89 |
| Everolimus (RAD001) | Change From Baseline (Randomization) in Urine Protein/Creatinine Ratio | 21.9 mg/mmol | Standard Deviation 92 |
Secondary
Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System
Kidney disease outcomes quality initiative (K/DOQI) classification is based on glomerular filtration rate (GFR), abbreviated MDRD formula (mL/min/1.73m\^2) : Stage 1 : GFR \>= 90; Stage 2 = GFR was between 60-89; Stage 3 = GFR was between 30-59 ; Stage 4 = GFR was between 15-29; Stage 5 = GFR was \< 15 (or dialysis)
Time frame: At Week 24
Population: ITT population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value at D28 and a posterior value were available.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Tacrolimus | Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System | Stage 2 | 34 Patients | — |
| Tacrolimus | Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System | Stage 4 | 0 Patients | — |
| Tacrolimus | Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System | Stage 1 | 24 Patients | 27.89 |
| Tacrolimus | Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System | Stage 5 | 0 Patients | — |
| Tacrolimus | Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System | Stage 3 | 28 Patients | — |
| Everolimus (RAD001) | Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System | Stage 5 | 0 Patients | — |
| Everolimus (RAD001) | Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System | Stage 2 | 29 Patients | — |
| Everolimus (RAD001) | Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System | Stage 3 | 4 Patients | — |
| Everolimus (RAD001) | Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System | Stage 4 | 0 Patients | — |
| Everolimus (RAD001) | Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System | Stage 1 | 41 Patients | 92 |
Secondary
Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification
Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy. The severity of BPAR was categorized as : Mild (Banff grade I, RAI = 4 and 5) Moderate (Banff grade II, RAI = 6 and 7) Severe (Banff grade III, RAI = 8 and 9) Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted.
Time frame: at 12 week and 24 week
Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value at day 28 and a posterior value were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus | Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification | Week 12: Mild | 1 Patients |
| Tacrolimus | Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification | Week 12: Moderate | 1 Patients |
| Tacrolimus | Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification | Week 12: Severe | 0 Patients |
| Tacrolimus | Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification | Week 24: Mild | 1 Patients |
| Tacrolimus | Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification | Week 24: Moderate | 1 Patients |
| Tacrolimus | Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification | Week 24: Sever | 0 Patients |
| Everolimus (RAD001) | Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification | Week 24: Moderate | 3 Patients |
| Everolimus (RAD001) | Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification | Week 12: Mild | 1 Patients |
| Everolimus (RAD001) | Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification | Week 24: Mild | 5 Patients |
| Everolimus (RAD001) | Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification | Week 12: Moderate | 1 Patients |
| Everolimus (RAD001) | Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification | Week 24: Sever | 0 Patients |
| Everolimus (RAD001) | Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification | Week 12: Severe | 0 Patients |
Secondary
Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation
Baseline was Day 28 visit. This endpoint reports patients with total adverse events (any), serious adverse events, death and premature discontinuation.
Time frame: Baseline to 24 weeks
Population: The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus | Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation | Any Adverse events | 85 Patients |
| Tacrolimus | Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation | Serious Adverse events | 28 Patients |
| Tacrolimus | Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation | Death | 1 Patients |
| Tacrolimus | Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation | At least one AE led to premature discontinuation | 4 Patients |
| Everolimus (RAD001) | Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation | At least one AE led to premature discontinuation | 18 Patients |
| Everolimus (RAD001) | Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation | Any Adverse events | 81 Patients |
| Everolimus (RAD001) | Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation | Death | 2 Patients |
| Everolimus (RAD001) | Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation | Serious Adverse events | 42 Patients |
Secondary
Number of Patients With Death or Graft Loss
The graft was presumed to be lost on the day the patient was registered again on the waiting list, or the day he/she received a new graft.
Time frame: at week 24
Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value at day 28 and a posterior value were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus | Number of Patients With Death or Graft Loss | Graft Loss | 1 Patients |
| Tacrolimus | Number of Patients With Death or Graft Loss | Death | 1 Patients |
| Everolimus (RAD001) | Number of Patients With Death or Graft Loss | Graft Loss | 0 Patients |
| Everolimus (RAD001) | Number of Patients With Death or Graft Loss | Death | 1 Patients |
Secondary
Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR)
Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy.
Time frame: at 12 week and 24 week
Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value at Day 28 and a posterior value were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus | Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR) | Week 12, Treated BPAR | 2 Patients |
| Tacrolimus | Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR) | Week 24, Treated BPAR | 2 Patients |
| Tacrolimus | Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR) | Week 12, Not treated BPAR | 0 Patients |
| Tacrolimus | Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR) | Week 24, Not Treated BPAR | 0 Patients |
| Everolimus (RAD001) | Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR) | Week 12, Not treated BPAR | 0 Patients |
| Everolimus (RAD001) | Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR) | Week 12, Treated BPAR | 2 Patients |
| Everolimus (RAD001) | Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR) | Week 24, Not Treated BPAR | 1 Patients |
| Everolimus (RAD001) | Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR) | Week 24, Treated BPAR | 8 Patients |
Secondary
Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3
Biopsy proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted. The patients with treated or untreated BPAR having RAI score \> 3 were reported in this end point.
Time frame: At 24 weeks
Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value at day 28 and a posterior value were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus | Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3 | Not Treated BPAR: RAI score >3 | 0 Patients |
| Tacrolimus | Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3 | Not Treated BPAR: Missing RAI score | 0 Patients |
| Tacrolimus | Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3 | Treated BPAR: RAI score >3 | 2 Patients |
| Everolimus (RAD001) | Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3 | Not Treated BPAR: RAI score >3 | 0 Patients |
| Everolimus (RAD001) | Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3 | Not Treated BPAR: Missing RAI score | 1 Patients |
| Everolimus (RAD001) | Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3 | Treated BPAR: RAI score >3 | 8 Patients |
Secondary
Number of Patients With Treatment Failures
Incidence of treatment failures, assessed with composite criterion including treated biopsy proven acute rejection (tBPAR) with a rejection activity index (RAI) according to Banff classification \>3, graft loss or death at 6 months. Biopsy proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted. The graft was presumed to be lost on the day the patient was registered again on the waiting list, or the day he/she received a new graft.
Time frame: At week 12 and week 24
Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value at Day 28 and a posterior value were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus | Number of Patients With Treatment Failures | week 12, Treatment failures - NO | 91 Patients |
| Tacrolimus | Number of Patients With Treatment Failures | week 12, Treatment failures - YES | 2 Patients |
| Tacrolimus | Number of Patients With Treatment Failures | week 24, Treatment failures - NO | 89 Patients |
| Tacrolimus | Number of Patients With Treatment Failures | week 24, Treatment failures - YES | 4 Patients |
| Everolimus (RAD001) | Number of Patients With Treatment Failures | week 24, Treatment failures - YES | 9 Patients |
| Everolimus (RAD001) | Number of Patients With Treatment Failures | week 12, Treatment failures - NO | 88 Patients |
| Everolimus (RAD001) | Number of Patients With Treatment Failures | week 24, Treatment failures - NO | 81 Patients |
| Everolimus (RAD001) | Number of Patients With Treatment Failures | week 12, Treatment failures - YES | 2 Patients |